Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can face non-AIDS complications, partially driven by chronic immune activation. To define immune perturbations during ART-suppressed viral infection, we performed longitudinal single-cell transcriptomic and plasma proteomic analyses of rhesus macaques infected with SIVmac239M and treated with ART for 70 weeks. We identified broad, bi-phasic immune changes. Acute infection involves an interferon-driven signature, correlated with viral replication, which largely resolves with viral control. Cell-associated virus correlated with interferon-stimulated genes in most tissues; however, this was blunted in gut-associated lymph nodes, a feature that may contribute to reservoir persistence. Separate alterations manifest 54–66 weeks post-infection, after 40 weeks of viral suppression, including broad TGF-β and NF-κB signaling and discrete bursts of inflammatory monocytes, largely restricted to bone marrow. These data highlight the bi-phasic remodeling of long-term ART-suppressed HIV, identifying specific tissues and cell populations with dysregulation, with implications for the treatment of PLWH.